Alveolar macrophage and mycobacteria

肺泡巨噬细胞和分枝杆菌

• 批准号: 7283613
• 负责人: RAJAMOULI PASULA
• 金额: $ 33.73万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-22 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7283613
• 关键词: Acquired Immunodeficiency Syndrome; Alveolar; Alveolar Cell; Alveolar Macrophages; Animals; Antigen Presentation; Appendix; Ascaridil; Binding; Cells; Chemotherapy-Oncologic Procedure; Defect; Disease; Gene Transfer; Genus Mycobacterium; Host Defense; Immune response; Immunity; Immunodeficient Mouse; Immunosuppression; Individual; Infection; Infection prevention; Infectious Agent; Inflammatory; Interferon Type II; Interferons; Lung; Lymphocyte; Mediating; Morbidity - disease rate; Mouse Strains; Mus; Mycobacterium Infections; Mycobacterium avium Complex; Mycobacterium tuberculosis; Numbers; Opportunistic Infections; Organism; Pathogenesis; Phagocytosis; Protein Overexpression; Resistance; Role; Silicosis; Steroids; T-Lymphocyte; TNF gene; Testing; Therapeutic immunosuppression; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Virulent; autocrine; body system; cytokine; gene therapy; human TNF protein; human subject; immunosuppressed; improved; in vivo; killings; macrophage; mortality; mycobacterial; novel strategies; paracrine; pathogen; prevent; receptor; reconstitution; response; success

DESCRIPTION (provided by applicant): Profound immunosuppression as occurs in HIV-infected subjects is frequently associated with complicating mycobacterial infections. Mycobacterium tuberculosis is a worldwide pathogen and is a major cause of morbidity and mortality in both normal and immunosuppressed subjects. Non-tuberculous mycobacteria such as M. avium can be opportunistic infections that infect immunosuppressed individuals or subjects with underlying disorders such as pulmonary silicosis. Regardless of whether mycobacteria are acting as pathogens or opportunistic infectious organisms, mycobacteria in the lung first infect alveolar macrophages (AMs), the resident inflammatory cell of the alveolar spaces. AMs must be primed and activated by cytokines such as IFN-gamma or TNF-alpha to maximally respond to infectious organisms such as mycobacteria. Although it is recognized that AMs are central to the pathogenesis of mycobacterial disease, there are few studies that have examined the role of AMs in vivo in response to mycobacterial infection. We have developed a novel approach to "reconstitute" normal and activated AMs into the lungs of immunodeficient animals. We will use this new approach to test the hypothesis Deficiencies in the response of AMs to mycobacteria such as MAC or M. tuberculosis permit initial lung infection and subsequent dissemination during immunosuppression; conversely, correction of these AM deficiencies will restore alveolar immunity, control lung infection and prevent dissemination. We will examine the underlying mechanisms by which AMs respond in vivo to mycobacterial infection and will then use a variety of strategies to activate AMs for reconstitution to see if alveolar host defense is restored and infection eradicated. This will also test whether AMs activated by pro-inflammatory cytokines such as IFN-gamma mediate alveolar host defense to mycobacteria by AM-derived TNF-alpha. These Specific Aims include: 1) to determine the mechanisms by which normal AMs reconstituted into the lungs of immunodeficient mice restore alveolar host defense to mycobacteria and prevent dissemination, 2) to determine if proinflammatory cytokines such as IFN-gamma are essential for alveolar host defense to mycobacteria and to prevent dissemination, 3) to determine if ex vivo gene therapy to reconstituted macrophages results in persistent overexpression of pro-inflammatory cytokines such as IFN-gamma in vivo and improves alveolar host defenses to mycobacteria and prevents dissemination, and 4) to determine if the effects of pro-inflammatory cytokines such as IFN-? on alveolar host defenses to mycobacteria are mediated by AM-derived TNF-alpha. This proposal will test hypotheses in vivo not possible by other means and will determine whether reconstitution of normal or activated AMs is sufficient to restore alveolar host defense to mycobacterial disease despite the presence of ongoing systemic immunosuppression.

描述（由申请人提供）： HIV 感染者中发生的严重免疫抑制常常与复杂的分枝杆菌感染相关。结核分枝杆菌是一种世界性病原体，是正常人和免疫抑制受试者发病和死亡的主要原因。非结核分枝杆菌（例如鸟分枝杆菌）可能是机会性感染，感染免疫抑制个体或患有肺矽肺等潜在疾病的受试者。无论分枝杆菌是病原体还是机会性感染生物，肺部的分枝杆菌首先感染肺泡巨噬细胞（AM），即肺泡腔的常驻炎症细胞。 AM 必须由 IFN-γ 或 TNF-α 等细胞因子启动和激活，才能最大程度地响应分枝杆菌等传染性生物体。尽管人们认识到AMs是分枝杆菌疾病发病机制的核心，但很少有研究探讨AMs在体内对分枝杆菌感染的反应中的作用。我们开发了一种新方法，可以将正常和激活的 AM“重建”到免疫缺陷动物的肺部。我们将使用这种新方法来检验以下假设：AMs 对分枝杆菌（如 MAC 或结核分枝杆菌）的反应缺陷导致最初的肺部感染和随后在免疫抑制期间的传播；相反，纠正这些 AM 缺陷将恢复肺泡免疫力，控制肺部感染并防止传播。我们将研究 AM 在体内响应分枝杆菌感染的潜在机制，然后使用各种策略激活 AM 进行重建，以观察肺泡宿主防御是否恢复并消除感染。这还将测试由促炎细胞因子（例如 IFN-γ）激活的 AM 是否介导 AM 衍生的 TNF-α 介导肺泡宿主对分枝杆菌的防御。这些具体目标包括：1) 确定在免疫缺陷小鼠肺部重建正常 AM 恢复肺泡宿主对分枝杆菌的防御并防止传播的机制，2) 确定促炎细胞因子（如 IFN-γ）对于肺泡宿主对分枝杆菌的防御和防止传播是否至关重要，3) 确定离体基因治疗是否可以重建 巨噬细胞导致体内促炎细胞因子（例如 IFN-γ）持续过度表达，并改善肺泡宿主对分枝杆菌的防御并防止传播，4）确定促炎细胞因子（例如 IFN-γ）是否会产生影响？肺泡宿主对分枝杆菌的防御是由 AM 衍生的 TNF-α 介导的。该提案将在体内测试通过其他方法不可能实现的假设，并将确定正常或活化的 AM 的重建是否足以恢复肺泡宿主对分枝杆菌疾病的防御，尽管存在持续的全身免疫抑制。

项目成果

Passive transfer of interferon-γ over-expressing macrophages enhances resistance of SCID mice to Mycobacterium tuberculosis infection.

干扰素γ过度表达巨噬细胞的被动转移增强了SCID小鼠对结核分枝杆菌感染的抵抗力。

• DOI: 10.1016/j.cyto.2017.02.009
• 发表时间: 2017
• 期刊: Cytokine
• 影响因子: 3.8
• 作者: Pasula,Rajamouli;Martin2nd,WilliamJ;Kesavalu,BanuRekha;Abdalla,MaherY;Britigan,BradleyE
• 通讯作者: Britigan,BradleyE

Airway delivery of silica increases susceptibility to mycobacterial infection in mice: potential role of repopulating macrophages.

二氧化硅的气道输送增加了小鼠对分枝杆菌感染的易感性：巨噬细胞再生的潜在作用。

• DOI: 10.4049/jimmunol.0803642
• 发表时间: 2009
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Pasula,Rajamouli;Britigan,BradleyE;Turner,Joanne;Martin2nd,WilliamJ
• 通讯作者: Martin2nd,WilliamJ

Airway delivery of interferon-γ overexpressing macrophages confers resistance to Mycobacterium avium infection in SCID mice.

气道输送干扰素-γ过度表达的巨噬细胞赋予 SCID 小鼠对鸟分枝杆菌感染的抵抗力。

• DOI: 10.14814/phy2.13008
• 发表时间: 2016
• 期刊: Physiological reports
• 影响因子: 2.5
• 作者: Pasula,Rajamouli;Britigan,BradleyE;Kesavalu,Banurekha;Abdalla,MaherY;Martin2nd,WilliamJ
• 通讯作者: Martin2nd,WilliamJ